Epigenetic programming of estrogen receptor in adipocytes by high-fat diet regulates obesity-induced inflammation
Rui Wu, Fenfen Li, Shirong Wang, Jia Jing, Xin Cui, Yifei Huang, Xucheng Zhang, Jose A. Carrillo, Zufeng Ding, Jiuzhou Song, Liqing Yu, Huidong Shi, Bingzhong Xue, Hang Shi
Rui Wu, Fenfen Li, Shirong Wang, Jia Jing, Xin Cui, Yifei Huang, Xucheng Zhang, Jose A. Carrillo, Zufeng Ding, Jiuzhou Song, Liqing Yu, Huidong Shi, Bingzhong Xue, Hang Shi
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Research Article Endocrinology Metabolism

Epigenetic programming of estrogen receptor in adipocytes by high-fat diet regulates obesity-induced inflammation

Abstract

Adipose inflammation plays a key role in obesity-induced metabolic abnormalities. Epigenetic regulation, including DNA methylation, is a molecular link between environmental factors and complex diseases. Here we found that high-fat diet (HFD) feeding induced a dynamic change of DNA methylome in mouse white adipose tissue (WAT) analyzed by reduced representative bisulfite sequencing. Interestingly, DNA methylation at the promoter of estrogen receptor α (Esr1) was significantly increased by HFD, concomitant with a downregulation of Esr1 expression. HFD feeding in mice increased the expression of DNA methyltransferase 1 (Dnmt1) and Dnmt3a and binding of DNMT1 and DNMT3a to Esr1 promoter in WAT. Mice with adipocyte-specific Dnmt1 deficiency displayed increased Esr1 expression, decreased adipose inflammation, and improved insulin sensitivity upon HFD challenge; mice with adipocyte-specific Dnmt3a deficiency showed a mild metabolic phenotype. Using a modified CRISPR/RNA-guided system to specifically target DNA methylation at the Esr1 promoter in WAT, we found that reducing DNA methylation at Esr1 promoter increased Esr1 expression, decreased adipose inflammation, and improved insulin sensitivity in HFD-challenged mice. Our study demonstrated that DNA methylation at Esr1 promoter played an important role in regulating adipose inflammation, which may contribute to obesity-induced insulin resistance.

Authors

Rui Wu, Fenfen Li, Shirong Wang, Jia Jing, Xin Cui, Yifei Huang, Xucheng Zhang, Jose A. Carrillo, Zufeng Ding, Jiuzhou Song, Liqing Yu, Huidong Shi, Bingzhong Xue, Hang Shi

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Figure 3

Inhibiting DNA methylation increases Esr1 expression and decreases inflammation in adipocytes.

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Inhibiting DNA methylation increases Esr1 expression and decreases infla...
(A and B) Pro-inflammatory gene expression in 3T3-L1 adipocytes with Esr1 knockdown (A) or overexpression (B), n = 3/group. *P < 0.05 vs. Scramble in A or pcDNA in B by Student’s t test. (C) Plasma glucose, insulin, glucose × insulin products, and insulin tolerance test (ITT) in DIO mice treated with 5-aza-dC (0.25 mg/kg BW, 3 times per week) for 6 weeks, n = 4–6/group. Groups labeled with different letters are statistically different from each other; *P < 0.05 vs. other groups. Statistical significance was analyzed by 1-way ANOVA with Fisher’s LSD post hoc test. (D) Esr1 and pro-inflammatory gene expression in gWAT of DIO mice treated with 5-aza-dC (0.25 mg/kg BW, 3 times per week) for 6 weeks, n = 5/group. Groups labeled with different letters are statistically different from each other as analyzed by Kruskal-Wallis nonparametric ANOVA by rank for Esr1 and ANOVA with Fisher’s LSD post hoc test for Tnfα and Il1β. All data are expressed as mean ± SEM.